Following mitochondrial outer membrane permeabilization during intrinsic apoptosis, cytochrome c enters the cytosol. What is the immediate consequence of cytosolic cytochrome c in the apoptotic cascade?

• A Direct proteolytic activation of executioner caspase-3 without intermediaries
• B Binding of SMAC to IAPs with immediate mitochondrial swelling
• C Binding to Apaf-1 to form the apoptosome, which recruits and activates procaspase-9 ✓
• D Cleavage of Bid to generate truncated Bid, amplifying the extrinsic pathway

Explanation

Cytosolic cytochrome c binds the adaptor protein Apaf-1 in the presence of dATP, forming a heptameric complex called the apoptosome. The apoptosome recruits procaspase-9 through CARD-CARD interactions, activating it as the initiator caspase of the intrinsic pathway, which then cleaves executioner caspases-3 and -7. Direct activation of caspase-3 requires an initiator caspase first. Truncated Bid is formed upstream by caspase-8 to link extrinsic signals to mitochondria, not downstream of cytochrome c release.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

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